Background: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications in the VHA, accounting for over 11 million 30-day prescriptions and nearly $50 million in medication costs annually. Though effective for treatment of acid-related disorders such as gastroesophageal reflux disease, PPIs have been associated with a number of potential harms in observational studies (e.g., dementia, chronic kidney disease, fractures), and increased mortality in Veterans. Nonetheless, PPIs continue to be used without an appropriate indication or for longer and at higher doses than necessary. Accordingly, VHA Pharmacy Benefits Management Services (PBM) will deploy RaPPID ? a national Randomized PPI De-prescribing program ? in Fiscal Year 2018 targeting patients for whom a short course of PPI is likely sufficient. This program will comprise activation of Clinical Pharmacy Specialists, provider education and academic detailing, and patient education. In partnership with PBM, we propose to conduct an evaluation of this national program in a cluster- randomized design. Objectives: (1) identify system-, provider-, and patient-level barriers and facilitators to PPI de-prescribing (formative evaluation); (2) assess the impact of the de-prescribing program on important clinical outcomes, and to understand how and why these outcomes were achieved or not achieved (outcomes and process evaluation); (3) assess the economic effects of the de-prescribing program (economic evaluation). Methods: Using formative evaluation approaches, we will first identify barriers and facilitators to uptake of RaPPID, prior to national randomization and deployment. We will then assess the impact of RaPPID on PPI use (primary outcome) in a cluster randomized design (cluster = healthcare system). We will also assess a variety of unintended effects, including impact of reduced PPI use on upper GI symptoms and complications such as upper GI bleeding. Furthermore, we will use process evaluation approaches to understand why and how the program was effective or ineffective in specific contexts. Finally, we will use data from the outcomes evaluation of this proposal to estimate the budget impact of RaPPID, taking into account the impact of the program on VHA and non-VHA healthcare utilization. Impact: RaPPID will be among the largest concerted efforts at de-prescribing ever undertaken in VHA. Prospective evaluation of the program therefore presents a unique opportunity not only to enhance the program itself, but also to gain insights about how to reduce the use of low-value services more broadly, a key VHA priority for the coming decade. Importantly, the prospective, controlled study design we propose will also allow us to make strong claims about whether PPIs cause the putative adverse effects to which they have been linked. Ultimately, this evaluation will provide not only valuable insight into the benefits and harms of a national effort to appropriately de-prescribe PPIs, but also broader lessons about how to effectively undertake other such interventions to de-implement entrenched clinical practices in the future.